Asthma, a disease of increasing prevalence and severity, is characterized by eosinophilic airway inflammation induced by excessive and inappropriate Th2 responses to environmental antigens. The "hygiene hypothesis" suggests that reduced rates of atopy and asthma in non-industrialized populations are due to protective "anti-atopic" responses to microbes. Although microbe-induced Th1 responses have been invoked as a mechanism of this protection, non-atopic individuals do not have elevated Th1 cytokines, and excessive Th1-type responses can be equally deleterious as Th2 responses. Moreover, even infections characterized by Th2 patterns, as is the case with helminths, are associated with reduced prevalence and severity of asthma and atopy. Recent studies have suggested that helminth infections induce regulatory-type immune responses; these responses may promote long-term tolerance against the development of atopic sensitization. The overall goal of this proposal is to investigate the mechanisms through which intestinal helminthes modulate atopic sensitization and airway inflammation in asthma. The central hypothesis is that intestinal helminthes can inhibit airway inflammation in asthma by induction of regulatory T-lymphocytes and/or regulatory dendritic cells. We will explore this hypothesis using a murine model of asthma in the following specific aims: Aim 1. Determine whether and how intestinal helminths prevent aberrant Th2 immune responses in the airway. A. Study the effect of intestinal worm exposure on a murine model of atopic asthma. B. Investigate if IL-10 or other soluble immunoregulatory cytokines are induced locally in the gut or in regional lymphoid tissues and mediate the protective process. C. Determine the cellular sources of these regulatory cytokines. Aim 2. Ascertain if helminths induce formation of regulatory T cells that mediate protection against atopic asthma. A. Identify and characterize regulatory T cells that appear in the lung after worm exposure. B. Study mechanisms leading to development of regulatory T cells. C. Determine if these regulatory T cells are sufficient to protect mice from Th2-mediated atopic asthma. In Aim I, we will examine the effects of helminths on manifestations of atopic asthma in a murine model, including the development of pulmonary Th2 cytokine production, airway eosinophilia, bronchial hyperresponsiveness, and antigen-specific immunoglobulin induction. We will study the induction of immunoregulatory cytokines, and identify the source of these mediators. Aim II will expand on these observations by testing the hypothesis that intestinal helminths induce regulatory cells (dendritic cells and/or regulatory T-lymphocytes) in the gut that migrate to the lung; we will determine how such regulatory cells limit pulmonary Th2 responses, study mechanisms leading to development of these cells and explore whether these cells can suffice to protect from asthma. Although completion of the second Aim is almost certainly beyond the scope of this two-year developmental research grant, these studies will be continued and extended through an R01 grant application. [unreadable] [unreadable]